Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Southwest Oncology Group (SWOG) Research Base
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00602459
First received: January 23, 2008
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

This randomized phase II trial is studying fludarabine and rituximab to compare how well they work with or without lenalidomide or cyclophosphamide in treating patients with symptomatic chronic lymphocytic leukemia. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving fludarabine and rituximab together with lenalidomide or cyclophosphamide may kill more cancer cells.


Condition Intervention Phase
B-cell Chronic Lymphocytic Leukemia
Stage I Chronic Lymphocytic Leukemia
Stage II Chronic Lymphocytic Leukemia
Stage III Chronic Lymphocytic Leukemia
Stage IV Chronic Lymphocytic Leukemia
Drug: fludarabine phosphate
Biological: rituximab
Drug: lenalidomide
Drug: cyclophosphamide
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS rate [ Time Frame: Interval between randomization and progression or death, whichever comes first, assessed up to 2 years ] [ Designated as safety issue: No ]
    Rates within arm will be estimated with their exact 90% confidence intervals. The chi-square test will be used to test whether the 2-year PFS of Arm B is significantly better than that of Arm A, and, secondarily, the log-rank test will be used to test for arm differences in time-to-progression.


Secondary Outcome Measures:
  • Response rate (complete remission {CR] and partial remission [PR]) [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    Induction response rates within each arm will be estimated with their exact 90% confidence intervals.

  • PFS rate of patients with del (11q22.3) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    PFS rate will be estimated with 90% confidence intervals and chi-square test will be used.

  • Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 16 months ] [ Designated as safety issue: Yes ]
    If a lower 90% confidence bound on the toxicity rate is > 0.20, then the toxicity data will be reviewed (confidence bound based on binomial distribution).

  • Differences in time-to-progression [ Time Frame: Time between randomization and progression or death, whichever comes first, assessed up to 2 years ] [ Designated as safety issue: No ]
    The log-rank test will be used to test for arm differences in time-to-progression. A Kaplan-Meier analysis will be used to describe the entire distribution of time-to-progression within each arm.

  • Correlation between interphase cytogenetic abnormalities with induction CR, PR, and PFS [ Time Frame: At baseline, 3 months after completion of induction therapy, 2 months after completion of lenalidomide, after 2 years, and at the time of relapse ] [ Designated as safety issue: No ]
    CR and PR rates will be estimated within marker-defined subgroups, and the difference in CR and PR rates between subgroups will be estimated with 95% confidence intervals. PFS will be estimated within marker-defined subgroups with the Kaplan-Meier method and PFS probabilities at given time points will be calculated with 95% confidence intervals.

  • Change across time from baseline to progression in clonal evolution, ZAP-70 expression, p53 dysfunction, gene expression-profile, and epigenetic changes in methylation [ Time Frame: At baseline, 3 months after completion of induction therapy, 2 months after completion of lenalidomide, after 2 years, and at the time of relapse ] [ Designated as safety issue: No ]
    Plotting means/medians (as in the case of ZAP-70) or proportions (as in the case of p53 expression) against time will be addressed. Analogous patient-specific plots will also be examined.

  • Correlation of flow cytometry negativity with PFS and overall survival [ Time Frame: At 24 months after the end of therapy ] [ Designated as safety issue: No ]
    PFS and OS will be estimated with the Kaplan-Meier method within subgroups defined by flow cytometry status at 24 months after enrollment; PFS probabilities at given time points will be calculated with 95% confidence intervals. A covariate adjusted hazard ratio will be calculated with the proportional hazards model.


Estimated Enrollment: 405
Study Start Date: January 2008
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (chemotherapy [chemo], monoclonal antibody therapy)
Patients receive rituximab IV on days 1, 3, and 5 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or orally on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (chemo, monoclonal antibody, immunomodulating therapy)
Patients undergo RI therapy as in arm I. Patients with a complete or partial response or stable disease proceed to RC therapy beginning approximately 4 months after completion of RI, comprising oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 3-6 courses in the absence of disease progression.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: lenalidomide
Given orally
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm III (chemotherapy, monoclonal antibody therapy)
Patients receive rituximab IV on days 1 and 3 of course 1 and on day 1 of all subsequent courses. Patients also receive fludarabine phosphate IV over 30 minutes or orally followed by cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm IV (chemo, monoclonal antibody, immunomodulating therapy)
Patients undergo the first course of RI therapy as in arm I or II, followed by rituximab IV on day 1 of all subsequent courses, and fludarabine IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Beginning approximately 4 months after completion of RI therapy, patients receive RC therapy comprising oral lenalidomide as in arm II.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: lenalidomide
Given orally
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria:

    • Absolute lymphocytosis > 5,000/μL

      • Lymphocytes must appear mature with < 55% prolymphocytes
    • Bone marrow aspirate smear must show > 30% of all nucleated cells as being lymphoid OR bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL

      • Overall cellularity must be normocellular or hypercellular
    • Lymphocyte phenotype must reveal predominant B-cell monoclonal population sharing a B-cell marker (i.e., CD19, CD20, or CD23) with the CD5 antigen, in the absence of other pan-T-cell markers

      • B-cells must be monoclonal with regard to expression of either kappa or lambda light chains and have surface immunoglobulin expression of low density

        • Patients with bright surface immunoglobulin levels must have CD23 co-expression
  • Must have symptomatic, active disease and meet 1 of the following risk criteria according to the modified three-stage Rai staging system:

    • Intermediate-risk disease (i.e., Rai stage I or II) with evidence of active disease as demonstrated by at least one of the following criteria:

      • Massive or progressive splenomegaly, hepatomegaly, and/or lymphadenopathy
      • Presence of weight loss > 10% within the past 6 months
      • Grade 2 or 3 fatigue
      • Fevers > 100.5° F or night sweats for > 2 weeks without evidence of infection
      • Progressive lymphocytosis with an increase of > 50% over a 2-monthperiod or an anticipated doubling time of < 6 months
    • High-risk disease (i.e., Rai stage III or IV)
  • Concurrent participation on CALGB-20702 (Leukemia Correlative Studies) required
  • Performance status 0-2
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use two effective methods of contraception for ≥ 4 weeks prior to, during, and for ≥ 4 weeks after completion of lenalidomide therapy (for patients randomized to arm II or IV)
  • Creatinine ≤ 1.5 times upper limit of normal
  • No medical condition requiring chronic use of oral corticosteroids
  • Patients with HIV infection may be eligible provided they meet the following criteria:

    • CD4-positive cell count > 350/mm³
    • HIV viral load< 10,000 copies HIV RNA/mL (if not on anti-HIV therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)
    • No evidence of hepatitis B or C infection
    • No evidence of resistant strains of HIV
    • No history of AIDS-defining condition
  • No prior therapy for CLL, including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL
  • No concurrent zidovudine or stavudine
  • No concurrent hormones or other chemotherapy, except steroids for hypersensitivity reactions or new adrenal failure or hormones for non-disease-related conditions (e.g., insulin for diabetes)
  • No concurrent chronic oral steroids
  • No concurrent palliative radiotherapy
  • No concurrent epoetin alfa or darbepoetin alfa during remission consolidation therapy (for patients randomized to arm II or IV)
  • Concurrent participation on CALGB-9665 allowed
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00602459

  Show 337 Study Locations
Sponsors and Collaborators
Southwest Oncology Group (SWOG) Research Base
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Investigators
Principal Investigator: John Byrd Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00602459     History of Changes
Other Study ID Numbers: NCI-2009-00441, NCI-2009-00441, CAN-NCIC-CL3, CALGB-10404, CDR0000584205, ECOG-10404, NCIC-CTG-C10404, SWOG-C10404, CALGB 10404, CALGB-10404, P30CA014236, U10CA031946
Study First Received: January 23, 2008
Last Updated: April 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Cyclophosphamide
Fludarabine monophosphate
Rituximab
Fludarabine
Lenalidomide
Vidarabine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on April 17, 2014